Quantifying changes in retinal non-perfusion over time with ultra-widefield fluorescein angiography following intravitreal treatment of diabetic retinopathy

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Abstract
Background: Diabetic Retinopathy (DR), a leading cause of preventable blindness, is conventionally evaluated using seven-field retinal fundus photography. Ultra-widefield fluorescein angiography (UWF FA) allows for detailed visualization and quantification of peripheral retinal non-perfusion (NP). This study aims to assess changes in NP and neovascularization (NV) following intravitreal anti-VEGF and steroid treatments using UWF FA. Methods: This retrospective, single-center cohort study included 65 eyes from 45 patients with Type 1 or 2 diabetes mellitus (DM) and UWF FA images acquired across two visits. Images were manually segmented by masked, trained graders, annotating foveal avascular zone (FAZ), NP, and NV surface areas. Patient demographics, clinical history, and treatment details were extracted via chart review. Stepwise multivariate linear regression identified predictors of changes in FAZ, NP, and NV areas, while causal modeling estimated effects of anti-VEGF and steroid treatments over time. Results: Eyes treated with steroid injections ( N = 13) had decreased total and mid-periphery retinal NP areas compared to untreated eyes or eyes that received anti-VEGF alone (total change in NP area: 4.32 ± 24.66 vs. 32.30 ± 65.40 vs. 27.21 ± 42.09 mm 2 ; p < 0.05). Increased frequency of steroid injections predicted decreased FAZ area ( p = 0.0036). Longer duration between FAs was associated with larger NP areas by 0.87 mm 2 per additional month (95% CI, 0.25 to 1.5; p = 0.0072), whereas more steroid injections ( p = 0.035), DME on initial clinical presentation ( p = 0.013), and vitreous hemorrhage development ( p = 0.0002) were associated with decreased NP areas. Compared to eyes in type 1 diabetics, eyes with type 2 DM were associated with − 56.45 mm 2 smaller total NP areas over time (95% CI, -92.3 to -20.52; p = 0.0028). Causal analyses suggest each additional steroid injection was associated with a 31.38 mm 2 decrease in total NP area (95% CI, -58.14 to -4.62; p = 0.022). Anti-VEGF treatment ( N = 28) did not have a significant effect on FAZ (95% CI, -0.153 to 0.060; p = 0.40), NP (95% CI, -17.20 to 3.91; p = 0.22), or NV areas (95% CI, -0.391 to 0.282; p = 0.75). Conclusions: Compared to anti-VEGF, intravitreal steroids produced significant improvement in retinal perfusion. Quantitative biomarkers from UWF FA may provide an objective approach to assessing treatment response and DR severity over time. Trial registration: Not applicable.
Funding Information
  • VitreoRetinal Surgery Foundation Research Award
  • National Eye Institute (1R01EY034325, 1R01EY033000)
  • Alcon Research Institute Young Investigator Grant
  • University of Michigan MTRAC-FFMI Kickstart
  • Fight for Sight- International Retinal Research Foundation (FFSGIA16002)
  • Research to Prevent Blindness

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